Mutoh Tomoko, Mutoh Tatsushi, Nakamura Kazuhiro, Yamamoto Yukiko, Tsuru Yoshiharu, Tsubone Hirokazu, Ishikawa Tatsuya, Taki Yasuyuki
Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Graduate School of Psychology, Kobe Shoin Women's University, Kobe, Japan.
Clin Exp Pharmacol Physiol. 2017 Apr;44(4):463-469. doi: 10.1111/1440-1681.12718.
Early brain injury/ischaemia (EBI) is a serious complication early after subarachnoid haemorrhage (SAH) that contributes to development of delayed cerebral ischaemia (DCI). This study aimed to determine the role of inotropic cardiac support using milrinone (MIL) on restoring acute cerebral hypoperfusion attributable to EBI and improving outcomes after experimental SAH. Forty-three male C57BL/6 mice were assigned to either sham surgery (SAH-sham), SAH induced by endovascular perforation plus postconditioning with 2% isoflurane (Control), or SAH plus isoflurane combined with MIL with and without hypoxia-inducible factor inhibitor (HIF-I) pretreatment. Cardiac output (CO) during intravenous MIL infusion (0.25-0.75 μg/kg/min) between 1.5 and 2.5 hours after SAH induction was monitored with Doppler echocardiography. Magnetic resonance imaging (MRI)-continuous arterial spin labelling was used for quantitative cerebral blood flow (CBF) measurements. Neurobehavioral function was assessed daily by neurological score and open field test. DCI was analyzed 3 days later by determining infarction on MRI. Mild reduction of cardiac output (CO) and global cerebral blood flow (CBF) depression were notable early after SAH. MIL increased CO in a dose-dependent manner (P<.001), which was accompanied by improved hypoperfusion, incidence of DCI and functional recovery than Control (P<.05). The neuroprotective effects afforded by MIL or Control were attenuated by hypoxia-inducible factor (HIF) inhibition (P<.05). These results suggest that MIL improves acute hypoperfusion by its inotropic effect, leading to neurobehavioral improvement in mice after severe SAH, in which HIF may be acting as a critical mediator.
早期脑损伤/缺血（EBI）是蛛网膜下腔出血（SAH）后早期出现的一种严重并发症，可导致迟发性脑缺血（DCI）的发生。本研究旨在确定使用米力农（MIL）进行的强心支持在恢复EBI所致急性脑灌注不足以及改善实验性SAH后结局方面的作用。43只雄性C57BL/6小鼠被分为假手术组（SAH-假手术组）、通过血管内穿刺诱导SAH并加用2%异氟醚进行后处理的对照组，或SAH加异氟醚并联合使用MIL（有无缺氧诱导因子抑制剂（HIF-I）预处理）。在SAH诱导后1.5至2.5小时静脉输注MIL（0.25 - 0.75μg/kg/min）期间，用多普勒超声心动图监测心输出量（CO）。采用磁共振成像（MRI）-连续动脉自旋标记法进行脑血流量（CBF）定量测量。每天通过神经学评分和旷场试验评估神经行为功能。3天后通过MRI确定梗死情况来分析DCI。SAH后早期心输出量（CO）轻度降低和全脑血流量（CBF）降低明显。MIL以剂量依赖方式增加CO（P<0.001），与对照组相比，其伴随脑灌注不足改善、DCI发生率降低及功能恢复（P<0.05）。缺氧诱导因子（HIF）抑制可减弱MIL或对照组提供的神经保护作用（P<0.05）。这些结果表明，MIL通过其强心作用改善急性灌注不足，从而使重度SAH后小鼠的神经行为得到改善，其中HIF可能起关键介导作用。
